Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• the present invention relates to novel water soluble C-ring analogues of 20(S)-Camptothecin having the general formula 1.
• R 5 represents hydrogen, lower alkyl, substituted lower alkyl, lower aralkyl, hydroxymethyl, carboxymethyl, aminomethyl, substituted aminomethyl where the amino group may be mono or disubstituted in which both substituents are independent or combined together to form a cyclic ring system of a total of 5-6 atoms containing carbon and optionally one or two heteroatoms selected from oxygen, nitrogen or sulfur; and
• R 6 represents hydrogen, phenyl or benzyl where the phenyl group may be unsubstituted or substituted
• Camptothecin having the formula 3 is an alkaloid with strong antitumor activity, and was isolated from Camptotheca acuminata by Wall and co-workers in 1966.
• Camptothecin having the formula 3 is an alkaloid with strong antitumor activity, and was isolated from Camptotheca acuminata by Wall and co-workers in 1966.
• its development as a potential drug for cancer treatment had been abandoned due to unacceptable side effects on humans and due to its low water solubility as well as high toxicity problems.
• camptothecin analogues involving the modification of rings A-E or the introduction of a variety of substituents on all the five rings of camptothecin of the formula 3 [M. E. Wall et al., J. Med. Chem ., 36 , 2689 (1993); R. P. Hertzberg et al., J. Med. Chem. , 715 (1989); S. W. Sawada et al., Chem. Pharm. Bull. , 41 (2), 310 (1993)].
• camptothecin analogues prepared to date, only two of them namely, CPT-11 having the formula 4 [ Chem. Pharm. Bull., 39 , 1446 (1991)], topotecan of the formula 5 [ J. Med. Chem. , 34 , 98(1991)] were introduced as anti-cancer drugs in the market recently.
• Another compound namely, 9-aminocamptothecin of the formula 6 [ J . Med. Chem., 29 , 2358 (1986)], is currently undergoing extensive clinical trials.
• SAR Structure Activity Relationship
• camptothecin analogues prepared in the literature, it was established that the modification of substituents at C-9 and C-7 position of camptothecin of the formula 3 plays an important role in the enhancement of anticancer activity by imparting stability to the E-ring lactone [T. G. Burke et al., J. Med. Chem. 37 , 40 (1994)]. It has also been recognized that the open form of the lactone moiety, namely, 'the Carboxylate form' is less effective therapeutically than the closed 'Lactone form' [Hertzberg et al., J. Med. Chem. , 32 , 715(1989); J. M. Covey, C.
• the C-5 substituted camptothecins claimed by Sawada et al., (JP 58,154,584; US 4,513,138; US 4,473,692; US 4,545,880; US 4,339,282) have the structural formula 10, where R represents hydroxy, lower alkyl, lower alkoxy, acyloxy groups, R 1 represents hydrogen, methoxy at 9th position; hydrogen, hydroxy, lower alkoxy, acyloxy, SH, thioalkyl, thioacyl, nitro, amino, alkylamino, acylamino and halogen groups at 10th position and R 2 represents hydrogen, lower alkyl, lower aralkyl, CH 2 OH, COOH, COOMe, CH 2 OR' where R' represents lower alkyl or acyl group.
• the present invention provides a novel process for the preparation of various C-5 substituted 20(S)-camptothecin derivatives of the formula where R 6 has the meaning described above. Also, by virtue of the present invention, a second chiral center at C-5 position was introduced into the camptothecins of the general formula 2 without disturbing the existing 20-hydroxyl group, C-20(S) chiral center.
• the present invention particularly provides C-5-O-substituted water soluble analogues of 20(S)-Camptothecin having the formula 1, where R 1 , R 2 , R 3 , R 4 , R 5 and R 6 have the meaning described above. Throughout the present invention, the terms representing R 1 through R 6 in these compounds have the following definitions.
• lower alkyl denotes a univalent, branched or straight hydrocarbon chain containing 1 to 8 carbon atoms.
• Representative of the alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec.butyl tert.butyl pentyl, iso pentyl tert.pentyl, hexyl, isohexyl and octyl.
• lower alkenyl' represents a branched or straight hydrocarbon chain having sp or sp 2 carbon centers containing 1 to 8 carbon atoms.
• Representative of the alkenyl groups are vinyl, propenyl, butenyl pentenyl, isopropenyl, isobutenyl, proparginyl, hexenyl and octenyl.
• 'halogen' or 'halo' represents chlorine, bromine or fluorine.
• 'haloalkyl' denotes alkyl groups substituted with halogens, preferably fluorine, bromine or chlorine. Representative of the haloalkyl groups are chloroethyl, bromopropyl, fluoroethyl, trifluoroethyl, trichloroethyl and trifluorobutyl.
• lower alkoxy denotes lower alkyl groups as defined above attached via oxygen linkage to the rest of the molecule. Representative of those groups are methoxy, ethoxy; isopropoxy, tert.butoxy, hexoxy, heptoxy and octoxy.
• lower alkanoyl denotes lower alkyl or alkenyl groups as defined above attached via a carbonyl group to the rest of the molecule. Representative of those groups are acetyl, propionyl, propenoyl, crotanoyl, butanoyl, pentanoyl and isopentanoyl.
• aminoalkyl' represents the lower alkyl groups as defined above substituted with amino groups.
• Representative of the aminoalkyl groups are 2-aminopropyl, 4-aminobutyl, 5-aminopentyl.
• Amino groups may also be mono or disubstituted and the representative of these substituted amino groups are dimethylamino, diethylamino, dibenzylamino, ethylisopropylamino, pyrrolidino, piperidino, morphilino or piperizino.
• heteroatom' refers to oxygen, nitrogen or sulfur.
• 'aryl or heteroaryl' represents the groups of aromatic nature having 5 or 6 membered rings which may be selected from phenyl, biphenyl, naphthyl, pyridyl, quinoline, isoquinoline, indole, pyroll, furan, benzofuran, thiophene, pyramidine, piperizine, thiosolidine or imidazole.
• phenyl' group used in the present invention refers to those substituents which can be selected from the groups such as hydroxyl, lower alkyl, haloalkyl, phenyl, benzyl, halogen, lower alkoxy, thioalkoxy, benzyloxy, carboxyl, cyano, nitro, amido, amino, and alkylamino.
• substituents such as 4-hydroxyphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, N,N-dimethylaminophenyl, and 4-carbomethoxyphenyl.
• substituted alkyl' group used in the present invention refers to those substituents which can be selected from the groups such as hydroxyl, alkyl, haloalkyl, phenyl, benzyl, halogen, alkoxy, thioalkoxy, benzyloxy, carboxyl, carbonyloxy, cyano, nitro, amido, amino, and alkylamino.
• Examples of such groups are fluoroethyl, chloropropyl, hydroxyethyl, methoxypropyl, N,N-diethylaminoethyl, N-benzoylaminopropyl, trifluoroethoxyethyl, phenoxyethyl, carbomethoxyethyl, (p-fluorobenzoyloxy)ethyl, aminopropyl, and 2-thioethyl.
• substituted amino' group used in the present invention refers to those substituents which can be selected from the groups such as hydroxyl, alkyl, haloalkyl, benzyl, benzoyl, alkoxy, carboxyl, amido, amino, and alkylamino.
• substituents such as hydroxyl, alkyl, haloalkyl, benzyl, benzoyl, alkoxy, carboxyl, amido, amino, and alkylamino.
• substituents such as hydroxyl, alkyl, haloalkyl, benzyl, benzoyl, alkoxy, carboxyl, amido, amino, and alkylamino.
• substituents such as hydroxyl, alkyl, haloalkyl, benzyl, benzoyl, alkoxy, carboxyl, amido, amino, and alkylamino.
• Examples of such groups are N,N-diethylamino, N-benzoylamino,
• N-carboethoxyamino, and N-chloroethylamino groups are also substituents on the amino group.
• substituents on the amino group can be combined together to form 5 or 6-membered cyclic ring system represented by pyrrolidino, piperidino, piperizino, morphilino, imidazolino, or thiazolidino.
• R 5 represents hydrogen, lower alkyl, substituted lower alkyl, lower aralkyl, hydroxymethyl, carboxymethyl, aminomethyl, substituted aminomethyl where the amino group may be mono or disubstituted in which both substituents are independent or combined together to form a cyclic ring system of a total of 5-6 atoms containing carbon and optionally one or two heteroatoms selected from oxygen, nitrogen or sulfur; and
• R 6 represents hydrogen; phenyl or benzyl
• R 6 represents hydrogen or lower alkyl
• R 1 represents hydrogen or methoxy
• R 2 represents hydrogen, hydroxy, lower alkoxy, acyloxy, thioalkyl, SH, thioacyl, nitro, amino, alkylamino, acylamino and halogen
• R 3 and R 4 are hydrogen and R 5 represents hydrogen, lower alkyl, lower aralkyl, CH 2 OH, COOH, COOMe or CH 2 OR' where R' represents lower alkyl or acyl group which comprises,
• the methodology developed and described in the present invention has generated a new chiral center at C-S position in the compounds of formula 2 without disturbing the integrity of 20(S)- ⁇ -hydroxy E-ring lactone moiety.
• the process developed constitutes a novel, facile and versatile semi-synthetic method for the preparation of C-5 substituted known and novel camptothecin derivatives of the formula 1, starting from the compounds of formula 2.
• the compounds of the formula 1 prepared by the process of the present invention thus represents diastereomers containing the newly created C-5 chiral center.
• the compounds of the general formula 1 are isolated as a mixture of 20(S),5(R) and 20(S),5(S) diastereomers.
• the two diastereomers have also been separated into their single optically pure entities.
• a ring or A/B ring substituted 20(S)-camptothecin derivatives of the general formula 2 where R 1 , R 2 , R 3 , R 4 and R 5 have the meaning described above, used as starting materials in the present invention are widely known and prepared according to the prior art documented in the literature.
• 7-ethylcamptothecin, 10-hydroxycamptothecin, 9-nitrocamptothecin, 12-nitrocamptothecin, 10-hydroxy-7-ethylcamptothecin (SN-38), 9-amino-camptothecin, 9-methoxycamptothecin, 9-hydroxycamptothecin, 9-methoxy-7-ethylcamptothecin, 9-hydroxy-7-ethylcamptothecin, 10,11-methylenedioxycamptothecin, 10,11-ethylenedioxycamptothecin, 10-hydroxy-9- (N,N-dimethylaminomethyl)camptothecin were prepared according to the known literature methods [T. R.
• compounds of the formula 12 where R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are independently the same or different and have the meaning given above can be prepared, as mentioned in the step (i), by the reaction of the compounds of the formula 2 with the compounds having the formula R 6 -OH where R 6 represents hydrogen, lower alkyl, lower alkenyl, haloalkyl, hydroxyalkyl, (C 3 -C 7 ) cycloalkyl, in the presence of a strong acid and a ferric salt.
• the acids used in this reaction can be selected from perchloric acid, hydrochloric acid, nitric acid, sulfuric acid or Lewis acids such as boron-trifluoride, zinc chloride, tinchloride, titanium tetrachloride.
• the ferric salt used in the above reaction can be chosen from ferric nitrate, ferric ammonium sulfate, ferric chloride. In general, the above reaction may be affected at a temperature in the range of 40-150°C., preferably 60 to 120°C.
• step (ii) of the process of the present invention to separate the mixture of compounds of formulas 12 and 13 as prepared in the step (i) the mixture is subjected to preferably either crystallization or column chromatography technique using silica gel.
• the solvent mixtures used in the above mentioned methods may contain a combination of the organic solvents such as chloroform, ethyl acetate, methanol, ethanol, ether, acetone and hexane.
• the compounds of the formula 13 can also be obtained in step (iii) of the process of the present invention, by treating the compounds of the formula 12 with acids in combination with water at a temperature in the range of 40-120°C.
• the acids used for this purpose may be selected from hydrochloric acid, hydrobromic acid, sulfuric acid, p-toluenesulfonic acid, acetic acid and perchloric acid.
• the solvents used in the reaction may be methanol, ethanol, butanol, isopropanol or 1,4-dioxane.
• step (iv) of the process of the present invention compounds of the formula 13 were reacted with compounds of the formula R 6 -OH where R 6 has the meaning described above, in the presence of an acid medium at a temperature in the range of 20 to 140°C. to furnish the compounds of the formula 1.
• the acids used in the reaction may be selected from sulfuric acid, hydrochloric acid, acetic acid, p-toluenesulfonic acid, pyridinium-p-toluenesulfonic acid, camphorsulfonic acid, methanesulfonic acid, perchloric acid or Lewis acids such as titanium tetrachloride, BF 3 -etherate and zinc chloride.
• the solvents used in the reaction may be selected from hexane, benzene, toluene, xylene, chloroform, carbon tetrachloride, dichloroethane, dichloromethane and 1,4-dioxane.
• the present invention is of particular significance in developing C-5-substituted 20(S)-camptothecin derivatives as a new class of C-ring modified camptothecin analogues which are useful as anti-tumor and/or anti-viral agents.
• the present invention is also of particular significance as the process developed and described here is highly versatile and amenable for large scale preparation of these camptothecin derivatives having the general formula 1.
• R 1 is nitro, amino, aminoalkyl, hydroxy, methoxy
• R 2 is hydroxy, carbonyloxy, halo
• R 2 , R 3 combined together to represent methylenedioxy or ethylenedioxy
• R 4 is hydrogen or nitro
• R 5 is ethyl, aminomethyl or substituted aminomethyl
• R 6 is 2'-hydroxyethyl, alkoxyethyl, chloroethyl, fluoroethyl, trifluoro-ethyl, or aminoethyl or aminopropyl where amino group may be dimethylamino, diethylamino, pyrollidino, piperidino, morphilino, piperizino, imidazolino;
• Representative of the compounds of formula 1 are:
• Table 1A shows MTD in Swiss Albino mice, Lactone Stability in whole blood (after 3 hours), Solubility, Pharmacokinetics MTD, and In vitro activity after 1 hour exposure, for the compounds of Examples 11, 26 and 27.
• Table 1 presents in vitro cell line activity expressed as IC50 values for various 20(S)-camptothecin C-ring analogues prepared in the present invention.
• Charts 1 to 3 present the data compiled based on NCI mean graphs for total growth inhibition (TGI) of different types of human cancer cell lines for the compounds prepared in the examples 27, 28 and 43. Similar data compiled for topotecan based on NCI mean graph is also included for comparison purposes.
• the data presented in Tables 2 and 3 shows that the C-ring analogues of 20(S)-camptothecin prepared in the present invention exhibited anti-tumor activity equal or superior to topotecan towards certain cell lines of different cancer cell panels.
• Table 4 presents the data obtained for the compound prepared in the example 32 against AIDS related lymphoma(ARL) cell lines. All the compounds used in the NCI's in vitro anti-cancer screening programme are mixtures substantially containing both the diastereomers having 20(S),5(S) and 20(S),5(R) configurations in varied ratios.
• test compound was screened against a battery of 60 human cell lines obtained from eight organs.
• the cell suspensions that were diluted according to the particular cell type and the expected target cell density (5000-40,000 cells per well based on cell growth characteristics) were added into 96-well microtiter plates. Inoculates were allowed a preincubation period of 24h at 37°C. for stabilization. Dilutions at twice the intended test concentrations were added at time zero in 100- ⁇ l aliquots to microtiter plate wells. Usually test compounds were evaluated at five 10-fold dilutions. The highest well concentration used in the test is 10 -4 M.
• the cells are then incubated in the presence of drug (the test compound) for further 48h in 5% CO 2 atmosphere and 100% humidity.
• drug the test compound
• the adherent cells are fixed to the plate by means of trichloroacetic acid, and after a number of washes, the cell layer is treated with the protein stain Sulforhodamine B.
• the optical density which is proportional to protein mass is then read by automated spectrophotometric plate readers at a wavelength of 515 nm. Readings are transferred to a microcomputer and final reports are generated using especially developed software.
• the compounds of formula 1 of the present invention, and the pharmaceutically acceptable salts thereof as described above, and the compositions containing them, are useful as anti-cancer and anti-viral agents.
• Administration of the novel active compounds of the formula 1, in pure form or in an appropriate pharmaceutical composition can be carried out via any of the accepted modes of administration for serving similar utilities.
• administration can be, for example, orally, nasally, parenterally or topically, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, capsules, powders, solutions, suspensions, emulsions, creams, lotions, aerosols, ointments, injections or the like, preferably, in unit dosage forms suitable, for simple administration of precise dosages.
• the compositions will include a conventional pharmaceutical carrier, diluent or excipient and an active novel compound of formula 1 and, in addition, may include either medicinal agents, pharmaceutical agents, carriers, adjuvants, etc.
• Example 32 9-Hydrory-5-ethoxy camptothecin 6.68 IN Vitro activity of Example 32 against AIDS related Lymphoma (ARL) cell lines: CELL NAME GI50 TGI CCRF - CEM 0.318 1.83 RL 0.463 3.94 KD 488 0.246 2.28 AS 283 0.268 0.678 PA 682 0.456 7.23 SU-DHL-7 0.609 3.51
• Step 1 To a mixture of 20(S)-Camptothecin of the formula 3 (2g), ferric chloride (2g), dissolved in 80ml of methanol, 10ml of sulfuric acid was added dropwise and continued heating at 70°C. for 24h. Excess acid and methanol were removed under vacuum and the residue was extracted with ethylacetate. Organic layer was washed with water, brine and dried over anh.sodium sulfate. Concentration of the solvent afforded 1.8g of yellowish powder containing 5-methoxycamptothecin and 5-hydroxy camptothecin in the ratio of 5:1.
• Step 2 Separation of the mixture by silica gel column chromatography using methanolchloroform solvent mixture as eluent afforded 1.5g of 5-methoxycamptothecin and 300mg of 5-hydroxycamptothecin.
• Step 2 Separation of the mixture by column chromatography gave 1g of 5-ethoxy-7-ethyl-camptothecin and 100mg of 5-hydroxy-7-ethylcamptothecin; mp: 150°C; [ ⁇ ] D at 27°C.
• Step 1 To a mixture of 20(S)-Camptothecin of the formula 3 (1g), ferric chloride (1g), dissolved in 50ml of ethanol 12ml of BF 3 -etherate was added dropwise and continued heating at 85°C. for 40h. Excess acid and ethanol were removed under vacuum and the residue was extracted with ethylacetate. Organic layer was washed with water, brine and dried over anh.sodium sulfate. Concentration of the solvent afforded 1g of yellowish powder containing 17-ethoxycamptothecin and 5-hydroxycamptothecin in the ratio of 6:1.
• Step 2 Separation of this mixture by silica gel column chromatography using ethyl acetate hexane solvent mixture as eluent afforded 700mg of 5-ethoxycamptothecin and 120mg of previously prepared 5-hydroxycamptothecin; mp: 140°C.; [ ⁇ ] D , at 28°C.
• Step 1 To a mixture of 20(S)-Camptothecin of the formula 3(500mg), ferric chloride (500mg), dissolved in 15ml of n-butanol, sulfuric acid was added dropwise and continued heating at 100°C. for 20h. Excess acid and n-butanol were removed under vacuum and the residue was extracted with ethylacetate. Organic layer was washed with water, brine and dried over anh.sodium sulfate. Concentration of the solvent afforded powdery material.
• Step 2 Purification of the above material by silica gel column chromatography using ethylacetate-hexane solvent mixture as eluent afforded 300mg of 5-butoxycamptothecin and 50mg of previously prepared 5-hydroxycamptothecin; mp: 82°C.; [ ⁇ ] D at 28°C.
• Step 1 To a mixture of 20(S)-Camptothecin of the formula 3 (1g), ferric chloride (1g), dissolved in 25ml of 2-chloroethanol 5ml of sulfuric acid was added dropwise and continued heating at 90°C. for 24h. Excess acid and 2-chloroethanol were removed under vacuum and the residue was extracted with ethylacetate. Organic layer was washed with water, brine and dried over anh.sodium sulfate. Concentration of the solvent afforded 1.2g of brownish solid
• Step 1 To a mixture of 20(S)-Camptothecin of the formula 3 (0.5g), ferric chloride (0.5g), dissolved in 18ml of 2,2,2-trifluoroethanol, sulfuric acid was added dropwise and continued heating at 80°C. for 24h. Excess acid and trifluoroethanol were removed under vacuum and the residue was extracted with ethylacetate. Organic layer was washed with water, brine and dried over anh.sodium sulfate. Concentration of the solvent afforded 600mg of solid material.
• Step 2 The above solid material was purified by column chromatography to give 250mg of 5-trifluoroethoxycamptothecin of the formula 1 along with 150mg of previously prepared 5-hydroxycamptothecin of the formula 13; mp 188°C.
• Step 1 To a mixture of 20(S)-Camptothecin of the formula 3 (1g), ferric chloride (1g), dissolved in 10ml of ethylene glycol, 5ml of sulfuric acid was added dropwise and continued heating at 70°C. for 36h. Excess acid and ethylene glycol were removed under vacuum and the residue was extracted with ethylacetate. Organic layer was washed with water, brine and dried over anh.sodium sulfate. Concentration of the solvent gave 1.1g of yellowish powder.
• Step 2 To a mixture of 80mg of 5-hydroxy-7-ethylcamptothecin and 0.1ml of p-toluenesulfonic acid suspended in 12ml of benzene, 20mg of 2-fluoroethanol was added and heated the mixture to reflux temperature for 14h. Reaction was quenched with a drop of pyridine and extracted with ethyl acetate. Organic layer was washed with water, NaHCO 3 , brine and concentrated to dryness.
• Step 2 To a mixture of 250mg of 5-hydroxy-7-ethylcamptothecin and 10 ⁇ l of conc.sulfuric acid suspended in 25ml of dichloroethane, 0.5ml of ethylene glycol was added and heated the mixture to reflux temperature for 14h. Reaction was quenched with a drop of pyridine and extracted with ethyl acetate. Organic layer was washed with water and brine and concentrated to dryness.
• Step 2 To a mixture of 60mg of 10,5-dihydroxycamptothecin and 5mg of p-toluenesulfonic acid suspended in 10ml of dichloroethane, 25mg of ethylene glycol was added and heated the mixture to reflux temperature for 16h. Reaction was quenched with a drop of pyridine and extracted with ethyl acetate. Organic layer was washed with water and brine and concentrated to dryness.
• Step 2 12ml of 25%HCl was added to 200mg of 5-ethoxy-10-hydroxy-7-ethylcamptothecin dissolved in 10ml of ethanol and heated to reflux for 24h. Excess acid and ethanol were distilled off and the remaining residue was diluted with ethylacetate. The organic layer was washed with 5% NaHCO 3 solution and brine.
• Step 2 To a mixture of 100mg of 10,5-dihydroxy-7-ethylcamptothecin and 5mg of p-toluenesulfonic acid suspended in 10ml of dichloroethane, 50mg of ethylene glycol was added and heated the mixture to reflux temperature for 16h. Reaction was quenched with a drop of pyridine and extracted with ethyl acetate. Organic layer was washed with water and brine and concentrated to dryness.
• Step 2 To a mixture of 60mg of 5-hydroxycamptothecin and 5mg of p-toluenesulfonic acid suspended in 10ml of benzene, 15mg of 2-aminoethanol was added and heated the cure to reflux temperature for 14h. Reaction was quenched with a drop of pyridine and extracted with ethyl acetate. Organic layer was washed with water,
• Step 2 To a mixture of 85mg of 7-ethyl-5-hydroxycamptothecin and 5mg of p-toluenesulfonic acid suspended in 20ml of benzene, 11 mg of 2-aminoethanol was added and heated the mixture to reflux temperature for 10h. Reaction was quenched with a drop of pyridine and extracted with ethyl acetate. Organic layer was washed with water, NaHCO 3 , brine and concentrated to dryness. The residue was purified by silica gel column chromatography using methanol-chloroform as eluent to afford 65mg of 5-(2'-aminoethoxy)-7-ethylcamptothecin.
• Step 2 To a mixture of 50mg of 7-ethyl-5-hydroxycamptothecin and 0.05ml of sulfuric acid suspended in 20ml of benzene, 30mg of 3-dimethylamino-1-propanol was added and heated the mixture to reflux temperature for 12h. Reaction was quenched with a drop of pyridine and extracted with ethyl acetate. Organic layer was washed with water, NaHCO 3 , brine and concentrated to dryness.
• Step 2 To a mixture of 100mg of 7-ethyl-5-hydroxycamptothecin and 10mg of camphorsulfonic acid suspended in 25ml of benzene, 30mg of 1-(2-hydroxyethyl) pyrrolidine was added and heated the mixture to reflux temperature for 16h. Reaction was quenched with a drop of pyridine and extracted with ethyl acetate. Organic layer was washed with water, NaHCO 3 , brine and concentrated to dryness.
• Step 2 To a mixture of 500mg of 7-ethyl-5-hydroxycamptothecin and 0.1ml of conc.sulfuric acid suspended in 30ml of benzene, 700mg of 2-chloroethanol was added and heated the mixture to reflux temperature using Dean-Stork apparatus for 8h. Reaction was quenched with a drop of pyridine and extracted with ethyl acetate. Organic layer was washed with water, NaHCO 3 , brine and concentrated to dryness.
• Step 2 To a mixture of 100mg of 7-ethyl-5-hydroxycamptothecin and 0.1ml of conc.sulfuric acid suspended in 10ml of benzene, 50mg of 2-N,N-dimethylaminoethanol was added and heated the mixture to reflux temperature using Dean-Stark apparatus for 10h. Reaction was quenched with a drop of pyridine and extracted with ethyl acetate. Organic layer was washed with water, NaHCO 3 , brine and concentrated to dryness.
• Step 2 To a mixture of 53mg of 5-hydroxycamptothecin and 8mg of p-toluenesulfonic acid suspended in 16ml of benzene, 14mg of 4-aminobutanol was added and heated the mixture to reflux temperature for 10h. Reaction was quenched with a drop of pyridine and extracted with ethyl acetate. Organic layer was washed with water, NaHCO 3 , brine and concentrated to dryness.
• Step 2 To a mixture of 120mg of 5-hydroxycamptothecin and 0.13ml of sulfuric acid suspended in 18ml of chloroform, 20mg of ethyleneglycol monomethylether was added and heated the mixture to reflux temperature for 10h. Reaction was quenched with a drop of pyridine and extracted with ethyl acetate. Organic layer was washed with water, NaHCO 3 , brine and concentrated to dryness.
• Step 2 To a mixture of 50mg of 5-hydroxy-7-ethylcamptothecin and 10mg of p-toluenesulfonic acid suspended in 15ml of benzene, 18mg of 1-methyl-2-pyrrolidinoethanol was added and heated the mixture to reflux temperature for 8h. Reaction was quenched with a drop of pyridine and extracted with ethyl acetate. Organic layer was washed with water, NaHCO 3 , brine and concentrated to dryness.

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